Site Mobile Navigation

Cancer Gene Tests Turn Out to Be Far From Simple

When scientists identified two genes, BRCA-1 and BRCA-2, as the culprits in most hereditary cases of breast cancer, the discovery prompted much excitement and hope. Women with family histories of breast cancer would at last be able to determine if they, too, were likely to get the disease. And so armed, they could take preventive action.

But as with most highly promising developments in cancer, the decadelong story of the breast cancer genes, while it has revealed important insights and greatly increased scientists' knowledge, has turned out to be far from simple, both from a scientific perspective and a personal one.

From studying the behavior of the breast cancer genes, for example, researchers now know that a woman can inherit a high risk of breast cancer from her father as well as from her mother, so it is not enough to consider only the mother's cancer history when estimating a woman's risk.

In addition, the three mutations in BRCA-1 and BRCA-2 initially identified as rendering a woman highly prone to breast cancer have since multiplied into hundreds of mutations, each of which may confer a different degree of risk.

Mutations in the genes, for example, greatly increase a woman's risk of developing ovarian cancer, which is both harder to detect and much harder to cure than breast cancer. And a recent report in the Journal of the National Cancer Institute linked mutations in BRCA-2 to an increased risk of developing cancers of the prostate, pancreas, gallbladder, bile duct and stomach, as well as malignant melanoma. Other studies have suggested a modestly increased risk of colon cancer.

To complicate matters further, the same gene defect may not behave the same way in all families. In some families, in which few or no cases of cancer have yet occurred, the gene's ''penetrance'' -- that is, its tendency to express itself -- may be much lower than in other families, where several cases of breast or ovarian cancer have occurred in blood relatives.

Finally, many researchers strongly suspect that BRCA-1 and BRCA-2 are not the only genes that can go awry and raise the risk of breast cancer. As more is learned about the human genome, other breast cancer genes may show up.

One of the most common misconceptions about breast cancer is that some cases are genetically influenced and some are not. It is true that only a small percentage of all cancers, including breast cancer, is inherited, that is, the likelihood of getting them is transmitted at conception from parent to son or daughter, either through the egg or through the sperm that fertilized it. In such cases, the gene defect appears in every body cell, including blood cells.

But genetic defects are at work even in cancers that are not inherited: for a normal cell to become a cancer cell, a genetic mutation or deletion must first occur, destroying the mechanism that puts the brakes on the cell's ability to reproduce. As a result, cancer cells multiply endlessly, like the broom in the Disney version of ''The Sorcerer's Apprentice.''

As Dr. Michael G. Muto, director of the Familial Ovarian Cancer Center at the Dana-Farber Cancer Institute in Boston, and Dr. Janet E. Shepherd, a gynecologist in Boulder, Colo., pointed out in a journal article, ''Cancer is always a genetic disease.''

A mutation that allows uncontrolled cell growth can occur at any time during life, induced either directly or indirectly, by exposure to a toxic substance like tobacco smoke or to a chronic irritant like alcohol or stomach acid. Such mutations can also occur spontaneously, when a mistake is made during cell division that is not detected by the cell's built-in surveillance system.

A cancer-causing mutation in a breast or ovarian cell acquired during a woman's lifetime cannot be passed on to her children. But researchers studying the genetics of breast cancer say it is possible, even likely, that all breast cancers involve mutations in BRCA-1 or BRCA-2 but that in only a small percentage of these cases is the mutation inherited from a woman's mother or father. Dr. Mary-Claire King, geneticist at the University of Washington in Seattle, said, ''There is increasingly good evidence for a close connection between inherited and noninherited forms of breast cancer, although what that connection is is not yet clear.''

There are three main types of genes involved in cancer: oncogenes, tumor-suppressor genes and mismatch/repair genes.

Oncogenes dictate the production of proteins that stimulate normal cell growth. If a mutation occurs in an oncogene, cells can proliferate at a greatly accelerated rate. Excessive cell proliferation -- as, for example, might happen in an esophagus chronically exposed to stomach acid -- greatly increases the chance that mutations will occur that could result in cancer.

Tumor-suppressor genes, as their name implies, place brakes on cell division. If a mutation inactivates a tumor-suppressor gene, cell multiplication can continue unchecked. BRCA-1 and BRCA-2 are tumor-suppressor genes that seem to be especially important in controlling cell multiplication in the breast and ovaries.

An error has occurred. Please try again later.

You are already subscribed to this email.

The mismatch/repair genes have the job of correcting mistakes made in the cell's DNA when it is copied, which happens every time a cell divides to form a new cell. Because DNA is the stuff that genes are made of, when mismatch/repair genes do not function properly, mutations can accumulate in other genes, including oncogenes and tumor-suppressor genes.

One hereditary form of colon cancer, the kind that does not involve the formation of polyps, has been linked to mutations in mismatch/repair genes. These same mutations have also been linked to a three to four-fold risk of developing ovarian cancer.

In 1971, Dr. Alfred Knudson of Fox Chase Cancer Center in Philadelphia, proposed a scheme by which an inherited mutation might result in a predisposition to cancer. The scheme, called the two-hit hypothesis, still stands for many cancer genes, including BRCA-1 and BRCA-2. Each cell contains two copies of every gene, and for cancer to result, both copies must be abnormal, the hypothesis holds. Thus, an alteration must occur in each of the two genes inherited from a person's mother and father.

Consider, for example, a woman who has inherited a mutated gene from her mother and a normal one from her father. According to the two-hit hypothesis, cancer would develop only if something happens to the normal gene in a single breast cell or ovarian cell during the woman's life.

For cancers that are not inherited, the two-hit hypothesis suggests that alterations must occur in both copies of a normal gene. Because two hits are less likely than one to occur during a person's lifetime, the risk of an inherited breast cancer is much greater than the risk of a cancer that develops without any hereditary predisposition.

The risk of developing a nonhereditary breast cancer is about 12 percent; that of nonhereditary ovarian cancer only 1 to 2 percent. But for women who start life with one copy of the BRCA-1 gene already mutated, the risk of developing breast cancer by age 70 is as high as 85 percent, and the risk of developing ovarian cancer at any time in a woman's life is as high as 44 percent.

For a woman with an inherited BRCA-1 mutation, the risk of developing either breast cancer or ovarian cancer by age 70 has been estimated to be as high as 95 percent, which has prompted some women with a BRCA-1 mutation to have their breasts and ovaries removed while these organs are still healthy. The risk of breast cancer associated with BRCA-2 mutations is similar, and, although lower for ovarian cancer, it is still very much higher than for women born without one mutated gene. Unlike BRCA-1, BRCA-2 mutations increase a man's risk of developing breast cancer.

As genes go, BRCA-1 and BRCA-2 are huge. BRCA-1, on chromosome 17, has about 100,000 base pairs of DNA and codes for a protein made of 1,863 amino acids. BRCA-2, on chromosome 13, is twice that size; its protein contains 3,418 amino acids.

The very size of these genes leaves lots of opportunity for things to go wrong in the DNA base pairs that could cause the gene to malfunction. Thus far, more than 340 mutations in BRCA-1 have been identified, and most can disrupt the gene's tumor-suppressor ability. For BRCA-2, more than 100 mutations have been identified, and researchers expect that many others will be found that can impair the gene's function.

Only 1 in 400 Americans harbors an inherited mutation in BRCA-1 or BRCA-2. However, certain mutations in these genes have been identified as occurring with unusual frequency in Ashkenazi Jews, whose ancestors came from Eastern Europe. About 90 percent of Jews in the United States are of Ashkenazi origin. And more than 2 percent of Ashkenazi Jews have been found to carry one of three mutations in a DNA base: On the BRCA-1 gene, the loss of two nucleic acids in position 185 or the insertion of an extra nucleic acid in position 5382; on the BRCA-2 gene, the loss of one nucleic acid at position 6174. Just as dialing one wrong digit in a phone number connects the caller with the wrong person, these seemingly minor errors are enough to impair a gene's ability to function normally. Certain BRCA mutations also are found more often in people from some Scandinavian countries.

A number of laboratories can now test a blood sample for the presence of the three mutations common in Ashkenazi Jews, at a cost of about $400. Blood cells can also be analyzed for all the mutations thus far identified in BRCA-1 and BRCA-2, at a cost of $2,500. But the results, in terms of disease risk, are often much harder to interpret than for the mutations found in Ashkenazi Jews. And the results of such testing are most useful when a mutation found in a woman who has had cancer is also found in her still healthy blood relatives.

A woman with a family history of breast cancer is most likely to have a mutated BRCA gene if the cancers in her blood relatives occurred before menopause. In an analysis of 798 families, women who developed breast cancer before age 50 had a 25 percent chance of carrying a BRCA mutation if they had any blood relative who also developed the disease before age 50.

However, interpretive difficulties arise when a woman with a family history of breast or ovarian cancer tests negative for BRCA mutations. Dr. Kenneth Offit, director of clinical genetics at Memorial Sloan-Kettering Cancer Center in New York, explained that the cancers in the woman's family could have been the result of different genes than the ones that were tested for. Or the cancers may have been caused by some other nonhereditary factor.

Since by age 85 one in eight American women will get breast cancer and more than 90 percent of those cases are not hereditary, ''by chance alone, more than one woman in a given family may have breast cancer,'' Dr. Offit said.